Project Summary/Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) causes a life-threatening tick-borne disease in humans. The disease presents as a severe form of hemorrhagic fever with a case fatality rate of 10?40%. CCHFV outbreaks have spanned a wide geographic area ranging from Western and Central Asia, the Middle East, Africa and Southern Europe. Increasing global temperatures, migratory birds, and the international livestock trade have all potentially contributed toward the spread of Hyalomma ticks?the primary vector for CCHFV. Expanding endemic zones, widespread morbidity and significant mortality make CCHFV an acute threat to public health and thus is listed as a NIAID Category A priority pathogen. The viral genome encodes a glycoprotein precursor that is processed into two structural glycoproteins?Gn and Gc?and two secreted glycoproteins?a mucin-like domain and GP38. Protective antibodies have been isolated that target Gc or GP38, suggesting that these two proteins should be given priority for vaccine development. Here we propose to engineer Gc- and GP38-based immunogens that focus the immune response onto broadly conserved epitopes that are capable of eliciting protective antibody responses. To accomplish our goal, we will structurally characterize CCHFV glycoproteins and their interactions with human-derived antibodies, rationally engineer vaccine antigens based in part on the structural information, and characterize the immune responses elicited by these antigens in animal models. These results will be used to guide further improvements of the immunogens, including display on self-assembling multi-valent nanoparticles, and the most promising candidates will be evaluated in a lethal murine model of CCHFV challenge. Given our expertise, unique reagents, and preliminary data, we are confident that we can deliver a state-of-the-art subunit vaccine candidate with the potential to induce cross-reactive protective antibodies, thereby satisfying an unmet need against this NIAID Category A tick-borne pathogen.